Integrins are transmembrane .alpha..beta. heterodimer receptors that are expressed on a wide variety of cells and are involved in extracellular matrix interactions. There are eight known .beta. subunits and fourteen known .alpha. subunits, which associate in various combinations to form at least twenty receptors with different ligand specificities. The ligands for several of the integrins are adhesive extracellular matrix (ECM) proteins such as fibronectin, vitronectin, collagens and laminin.
It is becoming increasingly clear that the ECM influences gene expression and that changes in the expression of genes encoding matrix proteins alter the composition of the ECM. Integrins appear to mediate "messages" from the exterior of a cell to its interior, thereby inducing changes in gene expression. In this capacity, the integrins control many medically important biological phenomena, including cell migration during development, tissue repair, cancer cell differentiation, metastasis of tumor cells, platelet aggregation and homing of immune system cells and neuronal processes to target sites.
Many integrins, including .alpha..sub.5 .beta..sub.1, recognize the amino acid sequence RGD (arginine-glycine-aspartic acid), which is present in fibronectin and other adhesive proteins to which the integrins bind. Peptides and protein fragments containing the RGD sequence can be used to modulate the activity of the RGD-recognizing integrins.
Fibronectin is the only known protein ligand for the .alpha..sub.5 .beta..sub.1 integrin and the binding of fibronectin to this integrin is mediated by an RGD sequence. In contrast, the integrins, .alpha..sub.v .beta..sub.3 and .alpha..sub.IIb .beta..sub.3, which also recognize the RGD sequence, can bind many different adhesive proteins.
The .alpha..sub.5 .beta..sub.3 integrin is important in promoting the assembly of fibronectin matrix and initiating cell attachment to fibronectin. The .alpha..sub.5 .beta..sub.1 integrin also appears to have a crucial role in mediating the migration of cells. The use of ligands that are specific for the .alpha..sub.5 .beta..sub.1 integrin receptor may permit modulation and manipulation of cell migration in various medical situations, including during wound healing, tissue repair and tumor invasion. Thus, a need exists to develop drug-like ligands that selectively bind with high affinity to an individual integrin. The present invention satisfies this need and provides related advantages as well.